Peripheral administration of an anti-TNF-α receptor fusion protein counteracts the amyloid induced elevation of hippocampal TNF-α levels and memory deficits in mice.

Abstract Alzheimer’s disease has long been associated with increased inflammation in the brain. Activated microglia and increased production of the inflammatory cytokines such as TNF-α, have been proposed to contribute to the onset and progression of the disease. We investigated if systemic administration of an anti-tumor necrosis factor (TNF) biologic medication clinically validated for rheumatoid arthritis (RA), TNF receptor 2 fused to a Fc domain (TNFR2:Fc), could ameliorate the behavioral symptoms and decrease neuroinflammation in a non-transgenic mouse model mimicking some hallmarks of the disease. Seven days after a single intracebroventricular (icv) injection of aggregated amyloid beta 25 – 35 (9 nmoles), mice displayed significant cognitive deficit in spontaneous alternation (working memory) and inhibitory avoidance (long-term memory) tasks. Alternation percentage decreased from 72.4% ± 1.3 to chance level (52.6% ± 1.7); step-through retention latency decreased from 247 s to 144 s. Subcutaneous administration of 30 mg/kg TNFR2:Fc every second day post amyloid beta 25 – 35 icv administration counteracted the amyloid-induced decrease in alternation percentage (66.4 s ± 1.8) and the decreased step-through retention latency (248 s ± 9). Measurement of hippocampal TNF-α levels by ELISA after behavioral assessment showed significant elevation in animals injected with amyloid beta 25 – 35 relative to animals injected with control peptide. In animals treated with 30 mg/kg TNFR2:Fc, TNF-α levels in the hippocampus were reduced and were similar to control animals. These data suggest that peripheral administration of TNFR2:Fc counteracts amyloid-induced memory impairment and normalizes increased TNF-α levels in hippocampus of a non-transgenic mouse model of amyloid induced cognitive deficit.